This invention relates to imidazoquinoline compounds that have an amide containing substituent at the 1-position, and to pharmaceutical compositions containing such compounds. A further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals, and in the treatment of diseases, including viral and neoplastic diseases.
The first reliable report on the 1H-imidazo[4,5-c]quinoline ring system, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H-imidazo[4,5-c]quinolines were reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs. 85, 94362 (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-c]quinolines.
Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of which are incorporated herein by reference.
There continues to be interest in the imidazoquinoline ring system. For example, EP 894 797 describes imidazoquinoline compounds that bear an amide containing substituent at the 1-position. The active compounds of this series require a terminal amine substituent that may be incorporated into a heterocyclic ring. As another example, WO 00/09506 describes imidazopyridine and imidazoquinoline compounds that may have an amide or urea containing substituent at the 1-position. The compounds described in this publication as having utility contain a 1-substituent wherein the amide or urea nitrogen is part of a heterocyclic ring. Despite these attempts to identify compounds that are useful as immune response modifiers, there is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.
We have found a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Accordingly, this invention provides imidazoquinoline-4-amine and tetrahydroimidazoquinoline-4-amine compounds that have an amide containing substituent at the 1-position. The compounds which have been found to be useful inducers of cytokine biosynthesis are defined by Formulae (I), (Ia), and (Ib), which are defined in more detail infra. These compounds share the general structural formula (I): 
wherein R1, R2, and R are as defined herein for each class of compounds having formulas (I), (Ia), and (Ib). The invention also provides novel compounds of formulas (Ic), (Id), and (Ie) as defined herein, which compounds are also useful as immune response modifiers and which also have the same general structural formula (I) above.
The compounds of Formulae (I), (Ia), (Ib), (Ic), (Id), and (Ie) are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune response when administered to animals. This makes the compounds useful in the treatment of a variety of conditions such as viral diseases and tumors that are responsive to such changes in the immune response.
The invention further provides pharmaceutical compositions containing the immune response modifying compounds, and methods of inducing cytokine biosynthesis in an animal, treating a viral infection in an animal, and/or treating a neoplastic disease in an animal by administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) to the animal.
In addition, methods of synthesizing the compounds of the invention and intermediates useful in the synthesis of these compounds are provided.
As mentioned earlier, we have found that certain compounds induce cytokine biosynthesis and modify the immune response in animals. Such compounds are represented by Formulae (I), (Ia), (Ib), (Ic), (Id), and (Ie), as shown below.
The invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I): 
wherein
R1 is -alkyl-NR3xe2x80x94COxe2x80x94R4 or -alkenyl-NR3xe2x80x94COxe2x80x94R4 wherein R4 is aryl, heteroaryl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
-alkyl;
-alkenyl;
-alkynyl;
-(alkyl)0-1-aryl;
-(alkyl)0-1-(substituted aryl);
-(alkyl)0-1-heteroaryl;
-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94O-alkyl;
xe2x80x94O-(alkyl)0-1-aryl;
xe2x80x94O-(alkyl)0-1-(substituted aryl);
xe2x80x94O-(alkyl)0-1-heteroaryl;
xe2x80x94O-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94CO-aryl;
xe2x80x94CO-(substituted aryl);
xe2x80x94CO-heteroaryl;
xe2x80x94CO-(substituted heteroaryl);
xe2x80x94COOH;
xe2x80x94COxe2x80x94O-alkyl;
xe2x80x94CO-alkyl;
xe2x80x94S(O)0-2-alkyl;
xe2x80x94S(O)0-2-(alkyl)0-1-aryl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted aryl);
xe2x80x94S(O)0-2-(alkyl)0-1-heteroaryl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94P(O)(OR3)2;
xe2x80x94NR3xe2x80x94COxe2x80x94O-alkyl;
xe2x80x94N3;
-halogen;
xe2x80x94NO2;
xe2x80x94CN;
-haloalkyl;
xe2x80x94O-haloalkyl;
xe2x80x94CO-haloalkyl;
xe2x80x94OH;
xe2x80x94SH; and in the case of alkyl, alkenyl, or heterocyclyl, oxo;
or R4 is 
wherein R5 is an aryl, (substituted aryl), heteroaryl, (substituted heteroaryl), heterocyclyl or (substituted heterocyclyl) group;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
-alkyl-O-alkyl;
-alkyl-O-alkenyl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R3)2;
xe2x80x94COxe2x80x94N(R3)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94COxe2x80x94Oxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
each R3 is independently selected from the group consisting of hydrogen; C1-10 alkyl-heteroaryl; C1-10 alkyl-(substituted heteroaryl); C1-10 alkyl-aryl; C1-10 alkyl-(substituted aryl) and C1-10 alkyl;
n is 0 to 4;
and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective carrier.
The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (Ia): 
wherein
R1 is -alkyl-NR3xe2x80x94COxe2x80x94R4 or -alkenyl-NR3xe2x80x94COxe2x80x94R4 wherein R4 is aryl, heteroaryl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
-heterocyclyl;
-(substituted heterocyclyl);
-(alkyl)0-1heterocyclyl;
-(alkyl)0-1(substituted heterocyclyl);
xe2x80x94O-(alkyl)0-1heterocyclyl;
xe2x80x94O-(alkyl)0-1(substituted heterocyclyl);
xe2x80x94S(O)0-2-(alkyl)0-1heterocyclyl; and
xe2x80x94S(O)0-2-(alkyl)0-1(substituted heterocyclyl);
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
-alkyl-O-alkyl;
-alkyl-O-alkenyl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R3)2;
xe2x80x94COxe2x80x94N(R3)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94COxe2x80x94Oxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
each R3 is independently selected from the group consisting of hydrogen; C1-10 alkyl-heteroaryl; C1-10 alkyl-(substituted heteroaryl); C1-10 alkyl-aryl; C1-10 alkyl-(substituted aryl) and C1-10 alkyl;
n is 0 to 4;
and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
The invention further provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (Ib): 
wherein
R1 is -alkyl-NR3xe2x80x94COxe2x80x94R4 or -alkenyl-NR3xe2x80x94COxe2x80x94R4 wherein R4 is heterocyclyl which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
-alkyl;
-alkenyl;
-alkynyl;
-(alkyl)0-1-aryl;
-(alkyl)0-1-(substituted aryl);
-(alkyl)0-1-heterocyclyl;
-(alkyl)0-1-(substituted heterocyclyl);
-(alkyl)0-1-heteroaryl;
-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94O-alkyl;
xe2x80x94O-(alkyl)0-1-aryl;
xe2x80x94O-(alkyl)0-1-(substituted aryl);
xe2x80x94O-(alkyl)0-1-heterocyclyl;
xe2x80x94O-(alkyl)0-1-(substituted heterocyclyl);
xe2x80x94O-(alkyl)0-1-heteroaryl;
xe2x80x94O-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94CO-aryl;
xe2x80x94CO-(substituted aryl);
xe2x80x94CO-heteroaryl;
xe2x80x94CO-(substituted heteroaryl);
xe2x80x94COOH;
xe2x80x94COxe2x80x94O-alkyl;
xe2x80x94CO-alkyl;
xe2x80x94S(O)0-2-alkyl;
xe2x80x94S(O)0-2-(alkyl)0-1-aryl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted aryl);
xe2x80x94S(O)0-2-(alkyl)0-1-heterocyclyl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted heterocyclyl);
xe2x80x94S(O)0-2-(alkyl)0-1-heteroaryl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94P(O)(OR3)2;
xe2x80x94NR3xe2x80x94COxe2x80x94O-alkyl;
xe2x80x94N3;
-halogen;
xe2x80x94NO2;
xe2x80x94CN;
-haloalkyl;
xe2x80x94O-haloalkyl;
xe2x80x94CO-haloalkyl;
xe2x80x94OH;
xe2x80x94SH;
or R4 is 
wherein R5 is an aryl, (substituted aryl), heteroaryl, (substituted heteroaryl), heterocyclyl or (substituted heterocyclyl) group;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
-alkyl-O-alkyl;
-alkyl-O-alkenyl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R3)2;
xe2x80x94COxe2x80x94N(R3)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94COxe2x80x94Oxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
each R3 is independently selected from the group consisting of hydrogen; C1-10 alkyl-heteroaryl; C1-10 alkyl-(substituted heteroaryl); C1-10 alkyl-aryl; C1-10 alkyl-(substituted aryl) and C1-10 alkyl;
n is 0 to 4;
and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
The invention also provides compounds that are useful as immune response modifiers. One such class of compounds has structural Formula (Ic): 
wherein
R1 is -alkyl-NR3xe2x80x94COxe2x80x94R4 or -alkenyl-NR3xe2x80x94COxe2x80x94R4 wherein R4 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
-alkyl;
-alkenyl;
-alkynyl;
-(alkyl)0-1-aryl;
-(alkyl)0-1-(substituted aryl);
-(alkyl)0-1-heteroaryl;
-(alkyl)0-1-(substituted heteroaryl);
-(alkyl)0-1-heterocyclyl;
-(alkyl)0-1-(substituted heterocyclyl);
xe2x80x94O-alkyl;
xe2x80x94O-(alkyl)0-1-aryl;
xe2x80x94O-(alkyl)0-1-(substituted aryl);
xe2x80x94O-(alkyl)0-1-heteroaryl;
xe2x80x94O-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94O-(alkyl)0-1-heterocyclyl;
xe2x80x94O-(alkyl)0-1-(substituted heterocyclyl);
xe2x80x94CO-aryl;
xe2x80x94CO-(substituted aryl);
xe2x80x94CO-heteroaryl;
xe2x80x94CO-(substituted heteroaryl);
xe2x80x94COOH;
xe2x80x94COxe2x80x94O-alkyl;
xe2x80x94CO-alkyl;
xe2x80x94S(O)0-2-alkyl;
xe2x80x94S(O)0-2-(alkyl)0-1-aryl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted aryl);
xe2x80x94S(O)0-2-(alkyl)0-1-heteroaryl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94S(O)0-2-(alkyl)0-1-heterocyclyl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted heterocyclyl);
xe2x80x94P(O)(OR3)2;
xe2x80x94NR6xe2x80x94COxe2x80x94O-alkyl;
xe2x80x94N3;
-halogen;
xe2x80x94NO2;
xe2x80x94CN;
-haloalkyl;
xe2x80x94O-haloalkyl;
xe2x80x94CO-haloalkyl;
xe2x80x94OH;
xe2x80x94SH; and in the case of alkyl, alkenyl, or heterocyclyl, oxo;
or R4 is 
wherein R5 is an aryl, (substituted aryl), heteroaryl, (substituted heteroaryl), heterocyclyl or (substituted heterocyclyl) group;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
-alkyl xe2x80x94O-alkyl;
-alkyl-O-alkenyl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R6)2;
xe2x80x94COxe2x80x94N(R6)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94COxe2x80x94Oxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
R3 is selected from the group consisting of C1-10 alkyl-heteroaryl; C1-10 alkyl-(substituted heteroaryl); C1-10 alkyl-aryl; C1-10 alkyl-(substituted aryl) and C1-10 alkyl;
each R6 is independently selected from the group consisting of hydrogen; C1-10 alkyl-heteroaryl; C1-10 alkyl-(substituted heteroaryl); C1-10 alkyl-aryl; C1-10 alkyl-(substituted aryl) and C1-10 alkyl;
n is 0 to 4;
and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof.
Another class of compounds provided by the invention is described by Formula (Id): 
wherein
R1 is -alkyl-NR3xe2x80x94COxe2x80x94R4 or -alkenyl-NR3xe2x80x94COxe2x80x94R4 wherein R4 is aryl or heteroaryl which may be unsubstituted or substituted by one or more substituents selected from the group consisting of:
-alkyl;
-alkenyl;
-alkynyl;
-(alkyl)0-1-aryl;
-(alkyl)0-1-(substituted aryl);
-(alkyl)0-1-heteroaryl;
-(alkyl)0-1-(substituted heteroaryl);
-(alkyl)0-1-heterocyclyl;
-(alkyl)0-1-(substituted heterocyclyl);
xe2x80x94O-alkyl;
xe2x80x94O-(alkyl)0-1-aryl;
xe2x80x94O-(alkyl)0-1-(substituted aryl);
xe2x80x94O-(alkyl)0-1-heteroaryl;
xe2x80x94O-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94O-(alkyl)0-1-heterocyclyl;
xe2x80x94O-(alkyl)0-1-(substituted heterocyclyl);
xe2x80x94CO-aryl;
xe2x80x94CO-(substituted aryl);
xe2x80x94CO-heteroaryl;
xe2x80x94CO-(substituted heteroaryl);
xe2x80x94COOH;
xe2x80x94COxe2x80x94O-alkyl;
xe2x80x94CO-alkyl;
xe2x80x94S(O)0-2-alkyl;
xe2x80x94S(O)0-2-(alkyl)0-1-aryl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted aryl);
xe2x80x94S(O)0-2-(alkyl)0-1-heteroaryl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94S(O)0-2-(alkyl)0-1-heterocyclyl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted heterocyclyl);
xe2x80x94P(O)(OR3)2;
xe2x80x94NR3xe2x80x94COxe2x80x94O-alkyl;
xe2x80x94N3;
-halogen;
xe2x80x94NO2;
xe2x80x94CN;
-haloalkyl;
xe2x80x94O-haloalkyl;
xe2x80x94CO-haloalkyl;
xe2x80x94OH; and
xe2x80x94SH;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
-alkyl-O-alkyl;
-alkyl-O-alkenyl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R3)2;
xe2x80x94COxe2x80x94N(R3)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
each R3 is independently selected from the group consisting of hydrogen; C1-10 alkyl-heteroaryl; C1-10 alkyl-(substituted heteroaryl); C1-10 alkyl-aryl; C1-10 alkyl-(substituted aryl) and C1-10 alkyl;
n is 0 to 4;
and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof,
with the proviso that R4 is not an unsubstituted benzene ring, and that when R4 is a substituted benzene ring the substituents are selected from the group consisting of C1-20 alkyl, C2-20 alkoxy, C1-20 alkylthio, hydroxy, haloalkyl, haloalkylcarbonyl, haloalkoxy, C1-20 alkylcarbonyl, C1-20 alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, nitrile, C1-20 alkoxycarbonyl, C1-20alkanoyloxy, C1-20alkanoylthio, oxo and xe2x80x94(C1-10alkyl)-NR3xe2x80x94(C1-10alkyl)-R5,
wherein R5 is an aryl, (substituted aryl), heteroaryl, (substituted heteroaryl), heterocyclyl or (substituted heterocyclyl) group.
A further class of compounds provided by the invention is described by Formula (Ie): 
wherein
R1 is -alkyl-NR3xe2x80x94COxe2x80x94R4 or -alkenyl-NR3xe2x80x94COxe2x80x94R4 wherein R4 is an alkyl or alkenyl group that is substituted by one or more substituents selected from the group consisting of:
-alkynyl;
-(substituted aryl) wherein the substituent(s) are independently selected from the group consisting of alkyl, alkoxy, alkylthio, hydroxy, haloalkyl, haloalkylcarbonyl, haloalkoxy, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, nitrile, alkoxycarbonyl, alkanoyloxy, and alkanoylthio;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
xe2x80x94O-alkyl;
xe2x80x94O-(alkyl)0-1-(substituted aryl) wherein the substituent(s) are independently selected from the group consisting of alkyl, alkoxy, alkylthio, hydroxy, haloalkyl, haloalkylcarbonyl, haloalkoxy, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, nitrile, alkoxycarbonyl, alkanoyloxy, and alkanoylthio;
xe2x80x94O-(alkyl)0-1-heteroaryl;
xe2x80x94O-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94CO-aryl;
xe2x80x94CO-(substituted aryl);
xe2x80x94CO-heteroaryl;
xe2x80x94CO-(substituted heteroaryl);
xe2x80x94COOH;
xe2x80x94COxe2x80x94O-alkyl;
xe2x80x94CO-alkyl;
xe2x80x94S(O)0-2-alkyl;
xe2x80x94S(O)0-2-(alkyl)0-1-aryl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted aryl);
xe2x80x94S(O)0-2-(alkyl)0-1-heteroaryl;
xe2x80x94S(O)0-2-(alkyl)0-1-(substituted heteroaryl);
xe2x80x94P(O)(OR3)2;
xe2x80x94NR3xe2x80x94COxe2x80x94O-alkyl;
xe2x80x94N3;
xe2x80x94NO2;
xe2x80x94CN;
xe2x80x94O-haloalkyl;
xe2x80x94CO-haloalkyl;
xe2x80x94OH;
xe2x80x94SH; and oxo;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
-alkyl-O-alkyl;
-alkyl-O-alkenyl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R3)2;
xe2x80x94COxe2x80x94N(R3)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94COxe2x80x94Oxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;
-(substituted aryl);
-heteroaryl;
-(substituted heteroaryl);
-heterocyclyl;
-(substituted heterocyclyl);
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
each R3 is independently selected from the group consisting of hydrogen; C1-10 alkyl-heteroaryl; C1-10 alkyl-(substituted heteroaryl); C1-10 alkyl-aryl; C1-10 alkyl-(substituted aryl) and C1-10 alkyl;
n is 0 to 4;
and each
R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof.
Preparation of the Compounds
Imidazoquinolines of the invention can be prepared according to Reaction Scheme I where R, R1, R2 and n are as defined above.
In step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline of Formula II is reacted with an amine of Formula R1NH2 to provide a 3-nitroquinolin-4-amine of Formula III. The reaction can be carried out by adding amine to a solution of a compound of Formula II in a suitable solvent such as chloroform or dichloromethane and optionally heating. Many quinolines of Formula II are known compounds (see for example, U.S. Pat. No. 4,689,338 and references cited therein).
In step (2) of Reaction Scheme I a 3-nitroquinolin-4-amine of Formula III is reduced to provide a quinoline-3,4-diamine of Formula IV. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as isopropyl alcohol or toluene.
In step (3) of Reaction Scheme I a quinoline-3,4-diamine of Formula IV is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-imidazo[4,5-c]quinoline of Formula V. Suitable equivalents to carboxylic acid include acid halides, orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R2 substituent in a compound of Formula V. For example, triethyl orthoformate will provide a compound where R2 is hydrogen and triethyl orthoacetate will provide a compound where R2 is methyl. The reaction can be run in the absence of solvent or in an inert solvent such as toluene. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
In step (4) of Reaction Scheme I a 1H-imidazo[4,5-c]quinoline of Formula V is oxidized to provide a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula VI using a conventional oxidizing agent that is capable of forming N-oxides. Preferred reaction conditions involve reacting a solution of a compound of Formula V in chloroform with 3-chloroperoxybenzoic acid at ambient conditions.
In step (5) of Reaction Scheme I a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula VI is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula VII which is a subgenus of Formula I. Step (5) involves (i) reacting a compound of Formula VI with an acylating agent and then (ii) reacting the product with an aminating agent. Part (i) of step (5) involves reacting an N-oxide of Formula VI with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chlorides (e.g., benezenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred. Para-toluenesulfonyl chloride is most preferred. Part (ii) of step (5) involves reacting the product of part (i) with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is preferred. The reaction is preferably carried out by dissolving the N-oxide of Formula VI in an inert solvent such as dichloromethane, adding the aminating agent to the solution, and then slowly adding the acylating agent. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Alternatively, step (5) may be carried out by (i) reacting an N-oxide of Formula VI with an isocyanate and then (ii) hydrolyzing the resulting product. Part (i) involves reacting the N-oxide with an isocyanate wherein the isocyanato group is bonded to a carbonyl group. Preferred isocyanates include trichloroacetyl isocyanante and aroyl isocyanates such as benzoyl isocyanate. The reaction of the isocyanate with the N-oxide is carried out under substantially anhydrous conditions by adding the isocyanate to a solution of the N-oxide in an inert solvent such as chloroform or dichloromethane. Part (ii) involves hydrolysis of the product from part (i). The hydrolysis can be carried out by conventional methods such as heating in the presence of water or a lower alkanol optionally in the presence of a catalyst such as an alkali metal hydroxide or lower alkoxide. 
Compounds of the invention can also be prepared according to Reaction Scheme II where R, R2, R4 and n are as defined above and m is 1-20.
In Reaction Scheme II an aminoalkyl substituted 1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with an acid chloride of Formula IX to provide a compound of Formula X which is a subgenus of Formula I. The reaction can be carried out by adding a solution of the acid chloride in a suitable solvent such as pyridine or dichloromethane to a solution of a compound of Formula VIII either at ambient temperature or at a reduced temperature. Many 1H-imidazo[4,5-c]quinolin-4-amines of Formula VIII are known compounds, see for example U.S. Pat. No. 6,069,149 (Nanba), the disclosure of which is incorporated by reference herein; others can be readily prepared using known synthetic methods. Many acid chlorides of Formula IX are commercially available; others can be readily prepared using known synthetic methods. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
Compounds of the invention can also be prepared according to Reaction Scheme III where R, R2, R4 and n are as defined above and m is 1-20.
In Reaction Scheme III an aminoalkyl substituted 1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with an acid of Formula XI to provide a compound of Formula X which is a subgenus of Formula I. The reaction can be run at ambient temperature in a solvent such as dichloromethane or pyridine using a standard coupling reagent such as 1,3-dicyclohexylcarbodiimide or 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
Compounds of the invention can also be prepared according to Reaction Scheme IV where R, R2, R4 and n are as defined above and m is 1-20.
In Reaction Scheme IV an aminoalkyl substituted 1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with an acid anhydride of Formula XII provide a compound of Formula X which is a subgenus of Formula I. The reaction can be run at ambient temperature in an inert solvent such as dichloromethane in the presence of a base such as N,N-diisopropylethylamine or pyridine. Many acid anhydrides of Formula XII are commercially available; others may be readily prepared using known synthetic methods. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
Tertiary amides of the invention can be prepared according to Reaction Scheme V where R, R2, R3, R4 and n are as defined above except that R3 is other than hydrogen and m is 1-20.
In step (1) of Reaction Scheme V an aminoalkyl substituted 1H-imidazo[4,5-c]quinolin-4-amine of Formula VIII is reacted with an aldehyde of Formula XIII to provide a secondary amine of Formula XIV. Preferably, the reductive amination is carried out using sodium triacetoxyborohydride. The reaction can be carried out by adding the sodium triacetoxyborohydride to a solution of the amine and the aldehyde in an inert solvent such as dichloromethane. The secondary amine or a salt thereof can be isolated using conventional methods.
In step (2) of Reaction Scheme V the secondary amine of Formula XIV is acylated to provide a compound of Formula XV which is a subgenus of Formula I. The reaction can be carried out by reacting the secondary amine of Formula XIV with an acid, acid chloride or an acid anhydride according to the methods of Reaction Schemes III, II and IV above. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
Tetrahydroimidazoquinolines of the invention can be prepared according to Reaction Scheme VI where R2, R3 and R4 are as defined above and m is 1-20.
In step (1) of Reaction Scheme VI an aminoalkyl substituted 1H-imidazo[4,5-c]quinolin-4-amine of Formula XVI is reduced to provide an aminoalkyl substituted 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII. Preferably the reduction is carried out by suspending or dissolving the compound of Formula XVI in trifluoroacetic acid, adding a catalytic amount of platinum (IV) oxide, and then subjecting the mixture to hydrogen pressure. The reaction can conveniently be carried out on a Parr apparatus. The product or a salt thereof can be isolated using conventional methods.
In step (2) of Reaction Scheme VI an aminoalkyl substituted 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII is reacted to provide a compound of Formula XVIII which is a subgenus of Formula I. When R3 is hydrogen, the reaction can be carried out according to the methods described in Reaction Schemes II, III and IV above using a tetrahydroimidazoquinoline of Formula XVII in place of the imidazoquinoline of Formula VIII. When R3 is other than hydrogen, then the reaction can be carried out using the method described in Reaction Scheme V. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
Tetrahydroimidazoquinolines of the invention can also be prepared according to Reaction Scheme VII where R, R2, R3, R4 and n are as defined above and m is 1-20.
In step (1) of Reaction Scheme VII a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolinyl tert-butylcarbamate of Formula XIX is hydrolyzed to provide an aminoalkyl substituted 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XX. The reaction can be carried out dissolving the compound of Formula XIX in a mixture of trifluoroacetic acid and acetonitrile and stirring at ambient temperature. Alternatively, the compound of Formula XIX can be combined with dilute hydrochloric acid and heated on a steam bath. Tetrahydro-1H-imidazo[4,5-c]quinolinyl tert-butylcarbamates of Formula XIX can be prepared using the synthetic route disclosed in U.S. Pat. No. 5,352,784 (Nikolaides). The product or a salt thereof can be isolated using conventional methods.
In step (2) of Reaction Scheme VII an aminoalkyl substituted 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine of Formula XX is reacted to provide a compound of Formula XXI which is a subgenus of Formula I. When R3 is hydrogen, the reaction can be carried out according to the methods described in Reaction Schemes II, III and IV above using a tetrahydroimidazoquinoline of Formula XX in place of the imidazoquinoline of Formula VIII. When R3 is other than hydrogen, then the reaction can be carried out using the method described in Reaction Scheme V. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
Some compounds of Formula I can be readily prepared from other compounds of Formula I. For example, compounds wherein the R4 substituent contains a chloroalkyl group can be reacted with an amine to provide an R4 substituent substituted by a secondary or teriary amino group; compounds wherein the R4 substituent contains a nitro group can be reduced to provide a compound wherein the R4 substituent contains a primary amine.
As used herein, the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d and the prefix xe2x80x9c-alkxe2x80x9d are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl and alkynyl groups containing from 2 to 20 carbon atoms. Preferred groups have a total of up to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl and adamantyl.
The term xe2x80x9chaloalkylxe2x80x9d is inclusive of groups that are substituted by one or more halogen atoms, including groups wherein all of the available hydrogen atoms are replaced by halogen atoms. This is also true of groups that include the prefix xe2x80x9chaloalk-xe2x80x9d. Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
The term xe2x80x9carylxe2x80x9d as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term xe2x80x9cheteroarylxe2x80x9d includes aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, pyrrolyl, tetrazolyl, imidazo, pyrazolo, oxazolo, thiazolo and so on.
xe2x80x9cHeterocyclylxe2x80x9d includes non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, and imidazolidinyl.
Unless otherwise specified, the terms xe2x80x9csubstituted arylxe2x80x9d, xe2x80x9csubstituted heteroarylxe2x80x9d and xe2x80x9csubstituted heterocyclylxe2x80x9d indicate that the rings or ring systems in question are further substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, hydroxy, halogen, haloalkyl, haloalkylcarbonyl, haloalkoxy (e.g., trifluoromethoxy), nitro, alkylcarbonyl, alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycloalkyl, nitrile, alkoxycarbonyl, alkanoyloxy, alkanoylthio, and, in the case of heterocyclyl, oxo.
In structural formulas representing compounds of the invention certain bonds are represented by dashed lines. These lines mean that the bonds represented by the dashed line can be present or absent. Accordingly, the compounds of the invention can be either imidazoquinoline compounds or tetrahydroimidazoquinoline compounds.
The invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, polymorphs, and the like.
Pharmaceutical Compositions and Biological Activity
Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound of the invention as described supra in combination with a pharmaceutically acceptable carrier.
The term xe2x80x9ca therapeutically effective amountxe2x80x9d means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction, antitumor activity and/or antiviral activity. Although the exact amount of active compound used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound as well as the nature of the carrier and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 xcexcg/kg to about 5 mg/kg, of the compound to the subject. Any of the conventional dosage forms may be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
The compounds of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, etc.
The compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
Cytokines whose production may be induced by the administration of compounds according to the invention generally include interferon-xcex1 (IFN-xcex1) and/or tumor necrosis factor-xcex1 (TNF-xcex1) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds of the invention include IFN-xcex1, TNF-xcex1, IL-1, 6, 10 and 12, and a variety of other cytokines. Among other effects, cytokines inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and tumors.
In addition to the ability to induce the production of cytokines, the compounds of the invention affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction. The compounds may also activate macrophages, which in turn stimulates secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes.
Compounds of the invention also have an effect on the acquired immune response. For example, although there is not believed to be any direct effect on T cells or direct induction of T cell cytokines, the production of the T helper type 1 (Th1) cytokine IFN-xcex3 is induced indirectly and the production of the T helper type 2 cytokines IL-4, IL-5 and IL-13 are inhibited upon administration of the compounds. This activity means that the compounds are useful in the treatment of diseases where upregulation of the Th1 response and/or downregulation of the Th2 response is desired. In view of the ability of compounds of the invention to inhibit the Th2 immune response, the compounds are expected to be useful in the treatment of atopic diseases, e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
The immune response modifying effects of the compounds make them useful in the treatment of a wide variety of conditions. Because of their ability to induce the production of cytokines such as IFN-xcex1 and/or TNF-xcex1, the compounds are particularly useful in the treatment of viral diseases and tumors. This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such as, but not limited to, viral diseases including genital warts; common warts; plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I and Type II; molluscum contagiosum; HIV; CMV; VZV; intraepithelial neoplasias such as cervical intraepithelial neoplasia; human papillomavirus (HPV) and associated neoplasias; fungal diseases, e.g. candida, aspergillus, and cryptococcal meningitis; neoplastic diseases, e.g., basal cell carcinoma, hairy cell leukemia, Kaposi""s sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin""s lymphoma, cutaneous T-cell lymphoma, and other cancers; parasitic diseases, e.g. pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, and leishmaniasis; and bacterial infections, e.g., tuberculosis, and mycobacterium avium. Additional diseases or conditions that can be treated using the compounds of the invention include eczema; eosinophilia; essential thrombocythaemia; leprosy; multiple sclerosis; Ommen""s syndrome; discoid lupus; Bowen""s disease; Bowenoid papulosis; and to enhance or stimulate the healing of wounds, including chronic wounds. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN-xcex2, TNF-xcex2, IL-1, 6, 10 and 12 that is increased over the background level of such cytokines. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 xcexcg/kg to about 5 mg/kg. The invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or composition of the invention to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 xcexcg/kg to about 5 mg/kg. An amount of a compound effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 xcexcg/kg to about 5 mg/kg.
The invention is further described by the following examples, which are provided for illustration only and are not intended to be limiting in any way.